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Molecular and Cellular Biology, May 2001, p. 3025-3036, Vol. 21, No. 9
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.9.3025-3036.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Caspase Cleavage Enhances the Apoptosis-Inducing Effects of BAD

Fabrizio Condorelli, Paolo Salomoni, Sophie Cotteret, Vincenzo Cesi, Srinivasa M. Srinivasula, Emad S. Alnemri, and Bruno Calabretta*

Department of Microbiology/Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Received 12 December 2000/Accepted 2 February 2001

The function of BAD, a proapoptotic member of the Bcl-2 family, is regulated primarily by rapid changes in phosphorylation that modulate its protein-protein interactions and subcellular localization. We show here that, during interleukin-3 (IL-3) deprivation-induced apoptosis of 32Dcl3 murine myeloid precursor cells, BAD is cleaved by a caspase(s) at its N terminus to generate a 15-kDa truncated protein. The 15-kDa truncated BAD is a more potent inducer of apoptosis than the wild-type protein, whereas a mutant BAD resistant to caspase 3 cleavage is a weak apoptosis inducer. Truncated BAD is detectable only in the mitochondrial fraction, interacts with BCL-XL at least as effectively as the wild-type protein, and is more potent than wild-type BAD in inducing cytochrome c release. Human BAD, which is 43 amino acids shorter than its mouse counterpart, is also cleaved by a caspase(s) upon exposure of Jurkat T cells to anti-FAS antibody, tumor necrosis factor alpha (TNF-alpha ), or TRAIL. Moreover, a truncated form of human BAD lacking the N-terminal 28 amino acids is more potent than wild-type BAD in inducing apoptosis. The generation of truncated BAD was blocked by Bcl-2 in IL-3-deprived 32Dcl3 cells but not in Jurkat T cells exposed to anti-FAS antibody, TNF-alpha , or TRAIL. Together, these findings point to a novel and important role for BAD in maintaining the apoptotic phenotype in response to various apoptosis inducers.

* Corresponding author. Mailing address: Department of Microbiology/Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107. Phone: (215) 503-4522. Fax: (215) 923-0249. E-mail: B_Calabretta{at}lac.jci.tju.edu.

Molecular and Cellular Biology, May 2001, p. 3025-3036, Vol. 21, No. 9
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.9.3025-3036.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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